RS56682B1 - Methods of administering an egfr inhibitor - Google Patents

Description

TECHNICAL FIELD

The invention relates to pharmaceutical compositions containing BIBW 29992 or its pharmaceutically acceptable salt for use in the treatment of a patient with non-small cell lung cancer where there is a step of avoiding or modifying the simultaneous administration of BIBW 2992 with P-glycoprotein (P-gp) inhibitors.

Also, the invention relates to BIBW 2992 or its pharmaceutically acceptable salt for use in a procedure for optimizing the therapeutic efficacy of treating NSCLC in human patients where there is a step of reducing the dose or dose frequency of a P-gp inhibitor or avoiding the complete administration of a P-gp inhibitor before starting the administration of BIBW 2992 or its pharmaceutically acceptable salt.

STATE OF THE ART

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been tested clinically to demonstrate efficacy in the treatment of certain cancers. Compounds that inhibit signal transduction with tyrosine kinases, for example the human EGF receptor, have been shown to be useful for the treatment of pathophysiological processes caused by hyperfunction of tyrosine kinases. David W. Fry, Pharmacol. Ther. Vol.82, No.2-3, pp.207-218, 1999. Several irreversible inhibitors have been shown to have therapeutic advantages such as prolonged tumor suppression when compared to reversible inhibitors such as gefitinib. DeBono & Rowinsky, No. Med. Bull.64:227-254 (2002). The compounds are disclosed in WO 02/50043, WO 2004/074263 and WO 2005/037824 as dual inhibitors of erbb1 receptor (EGFR) and erbB2 (Her2/neu) receptor tyrosine kinases, suitable for the treatment of e.g. benign or malignant tumors, primarily tumors of epithelial and neuroepithelial origin, metastases and abnormal proliferation of vascular endothelial cells (neoangiogenesis), for the treatment of diseases of the respiratory tract and lungs that are accompanied by increased or altered mucus production caused by stimulation by tyrosine kinase, as well as for the treatment of diseases of the gastrointestinal tract and bile duct and gall bladder that are associated with impaired tyrosine activity kinase.

BIBW 2992 is a highly selective, potent, irreversible tyrosine kinase inhibitor of EGFR and HER2 with promising efficacies seen in patients with non-small cell lung cancer (NSCLC). Drugs of the Future 2008, 33(8): 649-654; Li, D. et al, Oncogene (2008) 27, 4702–4711. BIBW 2992 pharmacokinetic (PK) characteristics after single and multiple doses reveal moderately rapid absorption British Journal of Cancer (2008) 98, 80–85. BIBW 2992 show a more than dose-proportional increase in exposure in healthy volunteers and cancer patients.

Skin toxicity and diarrhea are the most common adverse events in preliminary results of a Phase II clinical trial in patients with lung adenocarcinoma and activated EGFR mutations. Mukherji, D., et al., Expert Opin. Investig. Drugs (2009) 18(3), 293-300.

P-gp is a transmembrane efflux pump protein and appears to be an important component of the barrier that protects tissues from potentially harmful substances by pumping them out of cells. Standard chemotherapy treatment regimens for cancer usually include highly toxic compounds designed to kill tumor cells. In multidrug resistance (MDR), tumor cells will use P-gp to pump out the therapeutic drug before it can penetrate the tumor and effectively eliminate the cancer. Juranka PF et al., FASEB J. 1989 Dec;3(14):2583-92. While this has led to the development of agents that inhibit P-gp activity, this approach has been unanticipated since many randomized controlled trials evaluating P-gp substrate drugs used in combination with or without P-gp modulators have not shown significant improvements in outcome. Ferry DR et al., Eur J Cancer. 1996 Jun;32A(6):1070-81. Therefore, there may be other factors that limit the effectiveness of P-gp inhibitors in vivo. One study showed that the efficacy of P-gp inhibitors varies with cellular distance from blood vessels: P-gp overexpressing tumors have increased uptake of doxorubicin in proximal cells, minimal or no effect on drug uptake at intermediate distances from blood vessels, but reduced drug uptake in higher distal cells. Patel, Krupa J. et al., BMC Cancer 2009; 9: 356. The work to date on P-gp modulators used to enhance the efficacy of chemotherapeutic drugs has demonstrated the limitations and contingencies of such P-gp modulators and suggests the importance of considering drug distribution in the design and development of new treatment strategies.

BRIEF OVERVIEW OF THE INVENTION

The work cited above supports the principle that treating a patient with non-small cell lung cancer (NSCLC) with the EGFR inhibitor BIBW 2992 requires the active step of avoiding or modifying the concomitant use of such drugs with P-gp inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

The present invention reveals for the first time that taking both drugs together, a P-gp inhibitor and an EGFR inhibitor, results in an increase in drug exposure of said EGFR inhibitor. Concomitant administration of P-gp inhibitors together with EGFR inhibitors should be avoided and/or modified or the dose of EGFR inhibitors should be modified.

Alternatively, administration of a potent P-gp inhibitor at least 6 hours after administration of an EGRF inhibitor may minimize the DDI (drug-drug interaction) observed during co-administration of an EGFR inhibitor with a P-gp inhibitor.

Therefore, the invention provides a pharmaceutical composition containing BIBW 2992 or a pharmaceutically acceptable salt thereof, for use in the treatment of NSCLC patients, the procedure includes

(a) identifying a patient in need of treatment with BIBW 2992 or a pharmaceutically acceptable salt thereof;

(b) determining that the patient is receiving therapy with a P-gp inhibitor selected from alfentanil, amiloride, amiodarone, amitriptyline, astemizole, atovaquone, atorvastatin, azelastine, azidopine, azithromycin, bepridil, biricodar, bromocriptine, carbamazepine, carvedilol, chloroquine, chlorpromazine, clarithromycin, cyclosporine, cyproheptadine, darunavir, destilamiodarone, desipramine, dexniguldipine, dexrazoxane, diltiazem, dipyridamole, disulfiram, doxazosin, elacridar, emetine, erythromycin, felodipine, fenofibrate, fentanyl, flavonoids, fluoxetine, fluphenazine, fluvoxamine, fucidin, gallopamil, glyburide, gramicidin D, grapefruit juice, garlic, green tea, haloperidol, hydrocortisone, hyroxisine, josamycin, ketoconazole, imipramine, itraconazole, ivermectin, ketoconazole, lanquidar, lansoprazole, levothyroxine, lidocaine, loperamide, lopinavir, loratadine, lovastatin, maprotiline, mefloquine, methadone, mibefradil, midazolam, mitomycin C, nefazodone, nelfinavir, nicardipine, nitrendipine, nobiletin, norverapamil, omeprazole, orange juice, ofloxacin, paroxetine, pantoprazole, phenothiazines, phenobarbital, piperine, pimozide, probenecid, progesterone, promethazine, propafenone, propranolol, quercetin, quinacrine, quinidine, quinine, reserpine, ritonavir, saquinavir, sertraline, simvastatin, spironolactone, sufentanil, tacrolimus, tamoxifen, tarikidar, telithromycin, terfenadine, testosterone, tetrabenazine, thioridazine, trifluoperazine, trifluopromazine, trimipramine, valinomycin, vanadate, venlafaxine, verapamil, vinblastine, FK506, RU486 (mifepristone), valspodar PSC 833, zosuhidar and 2n-propylquinoline or their combinations;

(c) causing the patient's P-gp inhibitor therapy to be stopped prior to treatment with BIBW 2992 or a pharmaceutically acceptable salt thereof;

(d) administering BIBW 2992 or a pharmaceutically acceptable salt thereof to the patient; (e) resuming therapy with a P-gp inhibitor no earlier than 6 hours after administration of BIBW 2992 or a pharmaceutically acceptable salt thereof.

The invention further includes a pharmaceutical composition containing BIBW 2992 or a pharmaceutically acceptable salt thereof, for use in the treatment of a NSCLC patient by a method comprising

(a) determining that the patient is receiving therapy with a P-gp inhibitor selected from alfentanil, amiloride, amiodarone, amitriptyline, astemizole, atovaquone, atorvastatin, azelastine, azidopine, azithromycin, bepridil, biricodar, bromocriptine, carbamazepine, carvedilol, chloroquine, chlorpromazine, clarithromycin, cyclosporine, cyproheptadine, darunavir, destelamiodarone, desipramine, dexaniguldipine, dexrazoxane, diltiazem, dipyridamole, disulfiram, doxazosin, elacridar, emetine, erythromycin, felodipine, fenofibrate, fentanyl, flavonoids, fluoxetine, fluphenazine, fluvoxamine, fucidin, gallopamil, glyburide, gramicidin D, grapefruit juice, garlic, green tea, haloperidol, hydrocortisone, hyroxisine, josamycin, ketoconazole, imipramine, itraconazole, ivermectin, ketoconazole, lanihidar, lansoprazole, levothyroxine, lidocaine, loperamide, lopinavir, loratadine, lovastatin, maprotiline, mefloquine, methadone, mibefradil, midazolam, mitomycin C, nefazodone, nelfinavir, nicardipine, nitrendipine, nobiletin, norverapamil, omeprazole, orange juice, ofloxacin, paroxetine, pantoprazole, phenothiazines, phenobarbital, piperine, pimozide, probenecid, progesterone, promethazine, propafenone, propranolol, hercetin, quinacrine, quinidine, quinine, reserpine, ritonavir, saquinavir, sertraline, simvastatin, spironolactone, sufentanil, tacrolimus, tamoxifen, tarikidar, telithromycin, terfenadine, testosterone, tetrabenazine, thioridazine, trifluoperazine, trifluopromazine, trimipramine, valinomycin, vanadate, venlafaxine, verapamil, vinblastine, FK506, RU486 (mifepristone), valspodar PSC 833, zosuhidar and 2npropylquinoline or their combinations;

(b) reducing the doses or dose frequency of said P-gp inhibitor before starting the administration of BIBW 2992 or its pharmaceutically acceptable salt; and

(c) administering BIBW 2992 or a pharmaceutically acceptable salt thereof to the patient.

In another aspect of the invention, BIBW 2992 or a pharmaceutically acceptable salt thereof is provided for use in the process of optimizing the therapeutic efficacy of treating NSCLC in a human patient, which includes:

(a) determining that the patient is administered a P-glycoprotein (P-gp) inhibitor selected from alfentanil, amiloride, amiodarone, amitriptyline, astemizole, atovaquone, atorvastatin, azelastine, azidopine, azithromycin, bepridil, biricodar, bromocriptine, carbamazepine, carvedilol, chloroquine, chlorpromazine, clarithromycin, cyclosporine, cyproheptadine, darunavir, destilamiodarone, desipramine, dexniguldipine, dexrazoxane, diltiazem, dipyridamole, disulfiram, doxazosin, elacridar, emetine, erythromycin, felodipine, fenofibrate, fentanyl, flavonoids, fluoxetine, fluphenazine, fluvoxamine, fucidin, gallopamil, glyburide, gramicidin D, grapefruit juice, garlic, green tea, haloperidol, hydrocortisone, hyroxisine, josamycin, ketoconazole, imipramine, itraconazole, ivermectin, ketoconazole, lanihidar, lansoprazole, levothyroxine, lidocaine, loperamide, lopinavir, loratadine, lovastatin, maprotiline, mefloquine, methadone, mibefradil, midazolam, mitomycin C, nefazodone, nelfinavir, nicardipine, nitrendipine, nobiletin, norverapamil, omeprazole, orange juice, ofloxacin, paroxetine, pantoprazole, phenothiazines, phenobarbital, piperine, pimozide, probenecid, progesterone, promethazine, propafenone, propranolol, hercetin, quinacrine, quinidine, quinine, reserpine, ritonavir, saquinavir, sertraline, simvastatin, spironolactone, sufentanil, tacrolimus, tamoxifen, tarikidar, telithromycin, terfenadine, testosterone, tetrabenazine, thioridazine, trifluoperazine, trifluopromazine, trimipramine, valinomycin, vanadate, venlafaxine, verapamil, vinblastine, FK506, RU486 (mifepristone), valspodar PSC 833, zosuhidar and 2n-propylquinoline or their combinations;

(b) reducing the dose or dose frequency of said P-gp inhibitor or avoiding the complete administration of said P-gp inhibitor prior to commencing administration of BIBW 2992 or a pharmaceutically acceptable salt thereof; and

(c) administering BIBW 2992 or a pharmaceutically acceptable salt thereof to a subject having NSCLC.

In another solution, BIBW 2992 or its pharmaceutically acceptable salt according to any of the previous solutions is provided, where said BIBW 2992 or its pharmaceutically acceptable salt is administered in a dose of about 10 to 50 mg/day, preferably about 20 to 50 mg/day, preferably 40 mg/day, preferably in the form of a tablet, which is taken once a day.

In another embodiment, BIBW 2992 or a pharmaceutically acceptable salt thereof according to any of the preceding embodiments is provided, wherein BIBW 2992 or a pharmaceutically acceptable salt thereof is administered without food, meaning that it is taken at least one hour before a meal until at least 3 hours after a meal.

In another embodiment, BIBW 2992 or a pharmaceutically acceptable salt thereof according to any of the preceding embodiments is provided, wherein BIBW 2992 or a pharmaceutically acceptable salt thereof is formulated as a dispersible tablet/granule/pellet/powder.

In another embodiment, BIBW 2992 or a pharmaceutically acceptable salt thereof according to any of the preceding embodiments is provided, wherein the dispersible tablet/granules/pellets/powder is dispersible in an aqueous solvent, preferably water.

In another solution, BIBW 2992 or its pharmaceutically acceptable salt according to any of the previous solutions is provided, where BIBW 2992 or its pharmaceutically acceptable salt is formulated for oral administration after dispersing or dissolving said inhibitor, preferably with stirring, at least 5, preferably at least 10, even more preferably at least 5 min in an aqueous solvent, preferably water.

In another embodiment, BIBW 2992 or a pharmaceutically acceptable salt thereof according to any of the preceding embodiments is provided, wherein the BIBW 2992 or a pharmaceutically acceptable salt thereof is formulated for administration via a nasogastric tube.

In another aspect of the invention, BIBW 2992 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of NSCLC with a dosage regimen adjusted according to adverse events of said EGFR inhibitory treatment, concurrently with P-gp modulatory treatment, wherein said adverse event is monitored at a time point after the patient has started treatment with the EGFR inhibitor by measuring the amount and severity of adverse events as determined, for example, with CTCAE version 3.0 assessment

(http://ctep.cancer.gov/protocoldevelopment/electronic applications/docs/ctcaev3.pdf).

In another aspect of the invention, there is provided BIBW 2992 or a pharmaceutically acceptable salt thereof according to any of the preceding solutions, for use in the treatment of NSCLC where BIBW 2992 or a pharmaceutically acceptable salt thereof is a solid active anti-cancer ingredient.

Definitions

All terms used herein in this specification, unless otherwise indicated, are to be understood in their ordinary meaning as known in the art. Other more specific definitions are as follows:

The terms "ErbB1", "epidermal growth factor receptor" and "EGFR" are used interchangeably herein and refer to the natural sequence of EGFR as shown, for example, in Carpenter et al. Ann. Rev. Biochem. 56:881-914 (1987), including variants thereof (eg, a deletion mutant of EGFR as in Humphrey et al. PNAS (USA) 87:4207-4211 (1990)). erbB 1 refers to the gene encoding the EGFR protein product. As used herein, the EGFR protein is described as GenBank accession no. NP.sub.--005219 which is encoded by the erbB1 gene, GenBank accession no. NM.sub.—005228. See also W.J. Gullick et al., 1986, Cancer Res., 46:285-292;S. Cohen et al., 1980, J. Biol. Chem., 255:4834-4842; A. B. Schreiber et al., 1983, J. Biol. Chem., 258:846-853).

EGFR inhibitor includes reversible or irreversible EGFR inhibitors.

"Reversible EGFR" inhibitors include: 4-anilinoquinazoline, 4-[aralkylamino] pyridopyrimidine, and 4-phenylaminopyrrolo-pyrimidine structural classes. See David W. Fry, Pharmacol. Ther. Vol.82, No.2–3, pp.209–211, 1999. Specific examples include Gefitinib (compound ZD1839 "IRESSA"), Erlotinib (compound OSI-774, "TARCEVA"), Lapatinib, conventional cancer treatment with both IRESSA and TARCEVA involves daily oral administration of no more than 500 mg of the respective compounds.

"Irreversible EGFR inhibitor" includes any compound that binds irreversibly to EGFR, preferably to cysteine 773 of EGFR. Non-limiting examples include compounds described in U.S. Pat. Pat. No. 6,002,008, US 7,019,012, US 6,251,912, WO 02/50043, WO 2004/074263, WO 2005/037824, BIBW2992, EKB-569, HKI-272, HKI-357, Cl-1033, Icotinib or PF-00299804, which includes pharmaceutically acceptable salts thereof.

Preferred BIBW 2992 Dimaleate: 2-Butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-, (2E)-, (2Z)-2-butenedioate (1:2)

P-gp, is a P-glycoprotein encoded by the ABCB1 gene (Ueda K, Clark DP, Chen CJ, Roninson IB, Gottesman MM, Pastan I (January 1987). "The human multicellular resistance gene (mdr1). A cDNA that clones and initiates transcription". J. Biol. Chem. 262 (2): 505–8. PMID 3027054).

P-gp modulators include inhibitors as defined herein, preferably as compounds that are potent inhibitors of P-gp.

Potent P-gp inhibitors include any agent capable of preferably potently inhibiting P-gp. Non-limiting examples include alfentanil, amiloride, amiodarone, amitriptyline, astemizole, atovaquone, atorvastatin, azelastine, azidopine, azithromycin, bepidil, biricodar, bromocriptine, carbamazepine, carvedilol, chloroquine, chlorpromazine, clarithromycin, cyclosporine, cyproheptadine, darunavir, destilamiodarone, desipramine, dexniguldipine, dexrazoxane, diltiazem, dipyridamole, disulfiram, doxazosin, elicridar, emetine, erythromycin, felodipine, fenofibrate, fentanyl, flavonoids, fluoxetine, fluphenazine, fluvoxamine, fucidin, galpamil, glyburide, gramicidin D, grapefruit juice, garlic, green tea, haloperidol, hydrocortisone, hyroxisine, josamycin, ketoconazole, imipramine, itraconazole, ivermectin, ketoconazole, lanihidar, lansoprazole, levothyroxine, lidocaine, loperamide, lopinavir, loratadine, lovastatin, maprotiline, mefloquine, methadone, mibefradil, midazolam, mitomycin C, nefazodone, nelfinavir, nicardipine, nitrendipine, nobilitin, norverapamil, omeprazole, orange juice, ofloxacin, paroxetine, pantoprazole, phenothiazines, phenobarbital, piperine, pimozide, probenecid, progesterone, promethazine, propafenone, propranolol, hercetin, quinacrine, quinidine, quinine, reserpine, ritonavir, saquinavir, sertraline, simvastatin, spironolactone, sufentanil, tacrolimus, tamoxifen, tarichidar, telithromycin, terfenadine, testosterone, tetrabenzine, thioridazine, trifluoperazine, trifluopromazine, trimipramine, valinomycin, vanadate, venlafaxine, verapamil, vinblastine, FK506, RU486(mifepristone), valspodar PSC 833, Zosuhidar and 2n-propylquinoline and their combinations. Preferably Cyclosporine, Erythromycin, Ketoconazole, Itraconazole, Quinidine, Phenobarbital salt with Quinidine, Ritonavir, Valspodar or Verapamil.

"Modifying" the application of said P-gp modulators will be understood to mean reducing the dose or dose frequency of said P-gp modulators.

"Avoidance" of the full administration of said P-gp modulators shall be understood to mean either a) not starting administration of said P-gp modulators or b) stopping administration of said P-gp modulators and not resuming administration of said P-gp modulators.

Treatment may also include a combination of treatments, including but not limited to a tyrosine kinase inhibitor in combination with other tyrosine kinase inhibitors, chemotherapy, radiation, etc. In this regard, reference may be made to EP 09160202.9, PCT/EP/2010050338, WO 2008/121467, US 2009-0306101, US 2006-0058311, US 2005-0043233, US 2003-0225079 and US 2009-0318480.

The simultaneous use of a P-gp modulator in the treatment of a patient with a first drug such as an EGFR inhibitor means that the P-gp modulator is administered to the patient according to a treatment regimen characterized by repeated administration of the dosage unit at certain time intervals, e.g. once, twice or three times a day, in addition to a parallel, but independent treatment regimen characterized by repeated administration of the dosage unit of the first drug. In addition, the simultaneous use of a P-gp modulator together with an EGFR inhibitor means that both drugs will be administered in parallel (at the same time) or at most within a time frame of 1 hour between the use of both drugs.

Disclosures WO 02/50043, WO 2004/074263 and WO 2005/037824 cover the preparation as well as pharmaceutical formulations of the compounds. In addition, it is known for the treatment of tumor diseases that the compounds can be used in monotherapy or in combination with other antitumor therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide), mitosis inhibitors (e.g. vinblastine), compounds that interact with nucleic acids (e.g. cisplatin, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g.

5-FU etc.), cytokines (eg interferons) or antibodies.

The term "patient" refers to a human patient suffering from cancer and therefore in need of such treatment. In addition, the term "patient" should be understood to include such cancer patients bearing tumors with wild-type EGF receptor as well as preselected cancer patients with tumors harboring activating EGFR mutations. This can be located in the tyrosine kinase domain of the EGF receptor such as L858R or L861 targeted mutations in the activation linker (exon 21), or acceleration/insertion mutations in the ELREA sequence (exon 19), or a substitution at G719 located in the nucleotide linker (exon 18). In the extracellular domain of the EGF receptor, additional active mutations have been reported in different indications (eg EGFR vIII showing exon 2-7 deletion). Other mutations such as the T790M targeted mutation in exon 20 as well as certain insertions from exon 20 (eg D770_N771insNPG) that confer resistance to certain drugs should also be included, as well as double mutants such as the combined L858R / T790M mutation or exon-19-del/T790M.

The term "patient" should be understood to include cancer patients bearing tumors with a wild-type HER2 receptor, as well as preselected cancer patients with tumors that have activating HER2 mutations, e.g. M774_A775insAYVM.

The highest dose of BIBW 2992 is 160 mg once daily for 3 days or, alternatively, 100 mg once daily for 2 weeks.

The presence of certain gain-of-function mutations within the tyrosine kinase domain of the EGF receptor in a subset of NSCLC patients is associated with increased sensitivity to gefitinib and erlotinib therapy (Lynch, New England Journal Medicine 350, 2129 (2004); Paez, Science 304, 1497 (2004); Pao, Proceedings of the National Academy of Science of the United States 101, 13306 (2004)). Treatment with EGFR inhibitors can be first-line treatment, or next-line treatment, such as cancers initially diagnosed as sensitive to gefitinib / erlotinib or predicted to be sensitive to gefitinib / erlotinib by these methods. In particular, the L858R point mutation (exon 21), as well as a deletion/insertion mutation in the ELREA sequence (exon 19), accounts for the majority of gefitinib responses. A secondary point mutation in exon 20, T790M, is associated with acquired resistance to gefitinib or erlotinib. These mutations are analogous to the T315I mutations identified in CML patients relapsing under imatinib treatment (imatinib-resistant patients). Methods for detecting mutations in the tyrosine kinase domain of the EGF receptor are known in the art, several suitable diagnostic tools approved by the FDA and commercially available, e.g. an assay to detect epidermal growth factor receptor mutations in patients with non-small cell lung cancer (Genzyme Corp.; see also Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 24, Br 18S (June 20 Supplement), 2006: Abstract 10060).

Irreversible inhibitors as opposed to reversible inhibitors (eg, gefitinib) are able to inhibit proliferation and EGF-induced EGFR phosphorylation in cell lines expressing double mutant EGF receptors (Kwak, Proceedings of the National Academy of Science of the United States 102, 7665 (2005) and Kobayashi, New England Journal Medicine 352, 786 (2005)).

Each aspect of the present invention thus includes optionally preselected NSCLC patients for an EGFR mutation in the EGF receptor tyrosine kinase domain, as well as preselected NSCLC patients for a HER2 mutation. EGFR mutations that are preferably relevant in this context are selected from the group consisting of L858R and L861 targeted mutations in the activation loop (exon 21), frame deletion/insertion mutations in the ELREA sequence (exon 19), substitutions at G719 located in the nucleotide binding loop (exon 18), activating mutations in the extracellular domain of the EGF receptor such as EGFR vIII showing exon 2-7 deletion, T790M targeted mutation in exon 20, exon 20 insertion such as D770_N771insNPG, and double mutant such as combined L858R / T790M mutation and exon-19-del/T790M. A HER2 mutation preferably relevant in this context is the M774_A775insAYVM mutation.

Use in the treatment process:

The NSCLC treatment process will include preselection of NSCLC patients for EGFR and/or HER2 mutations and administration of a therapeutically effective amount of BIBW 2992 to a non-preselected NSCLC patient shown to carry an EGFR mutation in the EGF receptor tyrosine kinase domain and/or with a tumor that retains an activating HER2 mutation, optionally in combination with chemotherapy, biological therapy including therapeutic antibodies, targeted therapy including mTOR inhibitors, radiation, radioimmunotherapy and/or tumor resection by surgery. The method further comprises modifying or completely avoiding the administration of said P-gp inhibitors or inducers before commencing administration of BIBW 2992 or a pharmaceutically acceptable salt thereof.

Another method of treating NSCLC in a NSCLC patient by administering a therapeutically effective amount of BIBW 2992 to said NSCLC patient, optionally in combination with chemotherapy, biological therapy comprising therapeutic antibodies, targeted therapy comprising mTOR inhibitors, radiation, radio-immunotherapy and/or tumor resection by surgery, wherein said NSCLC patient is pre-selected based on a) having at least 12 weeks of treatment with a reversible EGFR inhibitor and b) having failed treatment with the specified reversible EGFR inhibitor. The procedure further includes modifying or completely avoiding the use of said P-gp inhibitors or inducers before starting the use of EGFR inhibitors.

BIBW 2992 can optionally be in the form of its tautomers, racemates, enantiomers, diastereomers and mixtures thereof and optionally in the form of its pharmacologically acceptable acid salts, solvates, hydrates, polymers or physiologically functional derivatives.

BIBW 2992 is administered orally, enterally, transdermally, intravenously, peritoneally or by injection, preferably orally. In any case, P-gp inhibitor/inducer should be avoided and/or modified.

Dosage:

BIBW 2992 can be administered to a human patient at a daily dose of 0.01-4 mg/kg body weight (bw), preferably 0.1-2 mg/kg, particularly preferably at a dose of 0.2-1.3 mg/kg bw. For eagle treatment, BIBW 2992 can be applied daily in a total dose of 10, 20, 30, 40, 50, 60, 70, 100, 200, or 300 mg, optionally divided into several doses, eg 1 to 3 doses to be administered during the day. Preferably, the oral daily dose is administered only once a day. In particular, the starting dose for BIBW 2992 is 40 mg, preferably in tablet form, once a day. For patients who tolerate a 40 mg starting dose, a 50 mg dose may be considered. For patients who already have TKI (tyrosine kinase inhibitor) treatment, the starting dose is 50 mg, preferably in tablet form, once a day. In particular, treatment periods with higher doses should be alternated with recovery periods, without the administration of BIBW 2992. For example, treatment can follow a "7 days on - 7 days off", "14 days on - 14 days off", "21 days on - 7 days off" or a continuous dosing schedule. The time period "with-without" can be chosen short, especially if larger doses are applied, or individually adapted to the needs of the patient. The preferred dose of BIBW 2992 is 20, 30, 40, 50 mg, most preferably 40 mg once a day.

Dose for intravenous administration e.g. BIBW2992MA2 can be 1 - 1000 mg, preferably 5 - 300 mg, especially preferably 10 - 100 mg (dosing refers to the base form of BIBW2992), either given as a bolus or, especially if higher doses are administered, as a slow intravenous infusion over several hours, e.g. for about 1, 2, 4, 6, 10, 12 or 24 hours.

In one solution, the invention relates to the method of treatment as described above, indicated by the fact that BIBW 2992, or its polymorph, metabolite, hydrate, solvent, individual optical isomer, mixture of its individual enantiomers or racemates, or its pharmaceutically acceptable salt, is administered alternately or in a daily dose so that the plasma level of the active substance preferably lies between 10 and 5000 nM for at least 12 hours dose interval.

However, it may optionally be necessary to deviate from the stated amounts, depending on body weight or the method of administration, the individual response to the drug, the nature of the formulation used, and the time and interval during which it is administered. Therefore, in some cases, it may be sufficient to use less than the minimum amount indicated previously, while in other cases the upper limit indicated will have to be increased. When applying a larger amount, it may be advisable to distribute it during the day in a larger number of individual doses.

Furthermore, the recommended intake for an EGFR inhibitor, preferably BIBW 2992, is without food and at least one hour before a meal or at least 3 hours after a meal.

BIBW 2992, its tautomers, racemates, enantiomers, diastereomers and its mixtures, and optionally its pharmacologically acceptable acid salts, solvates, hydrates, polymorphs, physiologically functional derivatives or prodrugs, can be used in individual therapy or in combination with other active substances according to the invention, optionally also in connection with other pharmacologically active substances.

Pharmaceutical formulations:

Suitable pharmaceutical preparations for use in accordance with the present invention include, for example, tablets, capsules, suppositories, solutions, and especially injectable (s.c., i.v., i.m.) solutions and infusions, syrups, emulsions or dispersible powders. The amount of pharmaceutically active compound in each case should be in the range of 0.1 - 90 wt.%, preferably 0.5 - 50 wt.% of the total composition, or in amounts sufficient to achieve the dosage range given below. The above doses can, if necessary, be given several times a day.

Suitable tablets can be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or delayed release agents such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. Tablets can also contain several layers.

Coated tablets can be prepared in accordance with the method of applying layers produced analogously to tablets with substances commonly used for tablet coatings, for example collidon or shellac, gum arabic, talc, titanium dioxide or sugar. In order to achieve a delayed release or to prevent incompatibility, the core can also consist of multiple layers. Similarly, the tablet coating may consist of multiple layers to achieve delayed release, possibly using the excipients listed above for tablets.

Syrups or elixirs containing active substances or their combinations may additionally contain sweeteners such as saccharin, cyclamate, glycerol or sugar and flavor enhancers, e.g. flavoring such as vanilla or orange extract. They may also contain suspending or thickening agents such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of preservatives such as p-hydroxybenzoates or stabilizers such as alkali metal salts of ethylenediamine tetrasyracetic acid, optionally using emulsifiers and/or dispersants, while if water is used as a diluent, organic solvents can optionally be used as solubilizers or auxiliary solvents, and transferred to injection vials or ampoules or infusion vials.

Capsules containing one or more active substances or combinations of active substances can, for example, be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packaged in gelatin capsules.

Suitable suppositories can be obtained, for example, by mixing with carriers intended for this purpose, such as neutral fats or polyethylene glycol or their derivatives.

Suitable excipients can be, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (eg petroleum fractions), oils of vegetable origin (eg nut oil or sesame oils), mono- or polyfunctional alcohols (eg ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolin, clay, talc, chalk), synthetic mineral powders (e.g. highly dispersed silica and silicates), sugar (e.g. glucose, lactose and dextrose), emulsifiers (e.g. lignin, spent sulfite liquor, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The preparations are applied in the usual way, preferably orally or transdermally, especially preferably orally. When administered orally, tablets may, of course, contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate, together with various additives, such as starch, preferably potato starch, gelatin and the like, in relation to the aforementioned carriers. Lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used to form tablets. In the case of aqueous suspensions, active substances can be combined with various flavor enhancers or colors, in addition to the mentioned excipients.

For parenteral use, solutions of active substances can be prepared using appropriate liquid carrier materials.

Preferred formulations and dosage forms for BIBW 2992 are disclosed in WO2005/037824 WO2009147238 and WO2011003853.

Examples:

The following examples are not intended, nor should they be construed, as limitations of the invention.

Example 1. Procedure for obtaining EGFR inhibitor.

Methods of making BIBW 2992 can be found in US 7,019,012, WO 2005/037824 and WO 2007/085638.

Example 2. Preclinical data indicating that BIBW2992 is a substrate of P-glycoprotein (P-gp)

Passive permeability through CaCo-2 cellular channels and P-gp transport profile:

Experiments were performed to evaluate its passive permeability and potential transport with P-glycoprotein (a.k.a. MDR1, ABCB1) and potential inhibition of P-gp with BIBW 2992.

BlBW 2992 exhibits high passive permeability and is a P-gp substrate (estimated Km 10-30 µM) as well as a P-gp inhibitor with an estimated Kiod of 3.4 µM (mean of two independent experiments).

Example 3. Clinical data indicating that BIBW2992 is a substrate of P-glycoprotein (P-gp)

Because BIBW 2992 was found to be a P-gp substrate in vitro (see above), investigators conducted a phase I analysis in healthy volunteers to evaluate the effects of the potent P-gp inhibitor ritonavir on the pharmacokinetics (PK) of BIBW 2992 (a P-gp substrate). In this open-label, randomized, two-way crossover study, the relative exposure after a single oral dose of BlBW 2992 (20 mg), coadministered with multiple oral doses of ritonavir (200 mg bid for 3 days), was compared to the exposure after a single oral dose of BIBW 2992 (20 mg) alone in a healthy male volunteer. The study was designed to determine the maximal effect of P-gp inhibition on the PK of BIBW 2992.

When BIBW 299220 mg was administered once daily in combination with ritonavir 200 mg twice daily, AUC0-BIBW 2992 increased by 47.6% (90% CI 133.7%, 162.9%), AUC0-tz increased by 49.0% (90% CI 134.5%, 165.1%), and Cmax increased by 38.5% (90% CI 120.6%, 158.9%) compared to BIBW 2992 when given alone. This is a surprising result. Due to this relatively high concentration in the micromolar range in correlation with the average maximum BlBW 2992 plasma concentrations at rest (I/Ki<0.1), drug-drug interactions based on P-gp inhibition with BIBW 2992 are considered less likely. The mean tmaxBIBW of 2992 was 4.00 hours with and without ritonavir. The distribution and elimination phases of BIBW 2992 do not appear to be affected by concomitant treatment with ritonavir. Also, the terminal half-life of BIBW 2992 remained unchanged.

As previous studies have revealed that metabolic reactions catalyzed by the enzyme CIP3A4 play a minor role for the metabolism of BIBW 2992 in vivo, and the N-demethylation of CIP3A4-N-demethylation of BIBW 2992 is too low to be quantitatively detected in healthy volunteers, the increase in exposure of BIBW 2992 in the presence of ritonavir is most likely attributed to the inhibition of P-gp-mediated transport processes during the absorption phase. BIBW 2992.

Due to these results, the following measures have been implemented for the clinical trials of BIBW 2992 as an amendment to the protocol which accuses that:

The use of strong P-gp inhibitors (including Cyclosporine, Erythromycin, Ketoconazole, Itraconazole, Quinidine, Phenobarbital salt with Quinidine, Ritonavir, Valspodar, Verapamil) and strong P-gp inducers (including preferably St John's wort, Rifampicin) must be avoided during treatment with BIBW 2992.

Example 4. Treatment of patients with pulmonary fibrosis using BIBW 2992 after failure with a reversible EGFR inhibitor

Patients with lung adenocarcinoma who had previously failed a reversible EGFR inhibitor (eg, gefitinib or erlotinib) and who had at least 12 weeks of therapy with said reversible inhibitor were identified as candidates for treatment with BIBW 2992. However, prior to treatment with BIBW 2992, some patients were found to be taking a potent P-gp inhibitor. Before starting treatment with BIBW 2992, treatment with a potent P-gp inhibitor was stopped. After this discontinuation of P-gp inhibitor treatment, treatment with BIBW 2992 was then started at a dose of 50 mg daily.

Example 5. BIBW 2992 treatment of lung cancer patients having tumors with EGFR mutations.

Lung adenocarcinoma patients harboring EGFR mutations (including but not limited to mutation-19 mutations, other exon 19 mutations, L858R mutations, other exon 21 mutations, exon 18 mutations, and exon 20 mutations) were identified as candidates for treatment with BIBW 2992. However, prior to treatment with BIBW 2992, some patients were found to be taking a potent P-gp inhibitor. Before starting treatment with BIBW 2992, treatment with a potent P-gp inhibitor was stopped. After this discontinuation of P-gp inhibitor treatment, treatment with BIBW 2992 was then started at a dose of 50 mg daily.

Claims (7)

Patent claims 1. A pharmaceutical composition containing BIBW 2992 or a pharmaceutically acceptable salt thereof, for use in the treatment of a patient with non-small cell lung cancer (NSCLC) by a procedure comprising (a) identifying a patient in need of treatment with BIBW 2992 or a pharmaceutically acceptable salt thereof; (b) determining that the patient is receiving therapy with a P-gp inhibitor selected from alfentanil, amiloride, amiodarone, amitriptyline, astemizole, atovaquone, atorvastatin, azelastine, azidopine, azithromycin, bepridil, biricodar, bromocriptine, carbamazepine, carvedilol, chloroquine, chlorpromazine, clarithromycin, cyclosporine, cyproheptadine, darunavir, destilamiodarone, desipramine, dexniguldipine, dexrazoxane, diltiazem, dipyridamole, disulfiram, doxazosin, elacridar, emetine, erythromycin, felodipine, fenofibrate, fentanyl, flavonoids, fluoxetine, fluphenazine, fluvoxamine, fucidin, gallopamil, glyburide, gramicidin D, grapefruit juice, garlic, green tea, haloperidol, hydrocortisone, hyroxisine, josamycin, ketoconazole, imipramine, itraconazole, ivermectin, ketoconazole, lanihidar, lansoprazole, levothyroxine, lidocaine, loperamide, lopinavir, loratadine, lovastatin, maprotiline, mefloquine, methadone, mibefradil, midazolam, mitomycin C, nefazodone, nelfinavir, nicardipine, nitrendipine, nobiletin, norverapamil, omeprazole, orange juice, ofloxacin, paroxetine, pantoprazole, phenothiazines, phenobarbital, piperine, pimozide, probenecid, progesterone, promethazine, propafenone, propranolol, hercetin, quinacrine, quinidine, quinine, reserpine, ritonavir, saquinavir, sertraline, simvastatin, spironolactone, sufentanil, tacrolimus, tamoxifen, tarichidar, telithromycin, terfenadine, testosterone, tetrabenazine, thioridazine, trifluoperazine, trifluopromazine, trimipramine, valinomycin, vanadate, venlafaxine, verapamil, vinblastine, FK506, RU486 (mifepristone), valspodar PSC 833, zosuhidar and 2npropylquinoline or their combinations; (c) causing the patient's P-gp inhibitor therapy to be stopped prior to treatment with BIBW 2992 or a pharmaceutically acceptable salt thereof; (d) administering BIBW 2992 or a pharmaceutically acceptable salt thereof to the patient; (e) continuation of treatment with a P-gp inhibitor no earlier than 6 hours after administration of BIBW 2992 or its pharmaceutically acceptable salt. 2. A pharmaceutical composition containing BIBW 2992 or a pharmaceutically acceptable salt thereof, for use in the treatment of a patient with non-small cell lung cancer (NSCLC) by a procedure comprising (a) determining that the patient is receiving therapy with a P-gp inhibitor selected from alfentanil, amiloride, amiodarone, amitriptyline, astemizole, atovaquone, atorvastatin, azelastine, azidopine, azithromycin, bepridil, biricodar, bromocriptine, carbamazepine, carvedilol, chloroquine, chlorpromazine, clarithromycin, cyclosporine, cyproheptadine, darunavir, destilamiodarone, desipramine, dexniguldipine, dexrazoxane, diltiazem, dipyridamole, disulfiram, doxazosin, elacridar, emetine, erythromycin, felodipine, fenofibrate, fentanyl, flavonoids, fluoxetine, fluphenazine, fluvoxamine, fucidin, gallopamil, glyburide, gramicidin D, grapefruit juice, garlic, green tea, haloperidol, hydrocortisone, hyroxisine, josamycin, ketoconazole, imipramine, itraconazole, ivermectin, ketoconazole, lanihidar, lansoprazole, levothyroxine, lidocaine, loperamide, lopinavir, loratadine, lovastatin, maprotiline, mefloquine, methadone, mibefradil, midazolam, mitomycin C, nefazodone, nelfinavir, nicardipine, nitrendipine, nobiletin, norverapamil, omeprazole, orange juice, ofloxacin, paroxetine, pantoprazole, phenothiazines, phenobarbital, piperine, pimozide, probenecid, progesterone, promethazine, propafenone, propranolol, hercetin, quinacrine, quinidine, quinine, reserpine, ritonavir, saquinavir, sertraline, simvastatin, spironolactone, sufentanil, tacrolimus, tamoxifen, tarichidar, telithromycin, terfenadine, testosterone, tetrabenazine, thioridazine, trifluoperazine, trifluopromazine, trimipramine, valinomycin, vanadate, venlafaxine, verapamil, vinblastine, FK506, RU486 (mifepristone), valspodar PSC 833, zosuhidar and 2npropylquinoline or their combinations; (b) reducing the dose or dose frequency of said P-gp inhibitor before starting the administration of BIBW 2992 or its pharmaceutically acceptable salt; and (c) administering BIBW 2992 or a pharmaceutically acceptable salt thereof to the patient. 3. Pharmaceutical composition for use in the process according to claim 1 or 2, where the P-gp inhibitor is selected from cyclosporine, erythromycin, ketoconazole, itraconazole, quinidine, phenobarbital salt with quinidine, ritonavir, valspodar and verapamil. 4. A pharmaceutical composition for use in a method according to claim 1, 2 or 3, wherein BIBW 2992 or its pharmaceutically acceptable salt is administered without food, which means taking at least one hour before a meal until at least 3 hours after a meal. 5. BIBW 2992 or its pharmaceutically acceptable salt, for use in a procedure for optimizing the therapeutic efficacy of treating NSCLC in a human patient, which includes: (a) ascertaining that the patient is receiving a P-glycoprotein (P-gp) inhibitor selected from among alfentanil, amiloride, amiodarone, amitriptyline, astemizole, atovaquone, atorvastatin, azelastine, azidopine, azithromycin, bepridil, biricodar, bromocriptine, carbamazepine, carvedilol, chloroquine, chlorpromazine, clarithromycin, cyclosporine, cyproheptadine, darunavir, destilamiodarone, desipramine, dexniguldipine, dexrazoxane, diltiazem, dipyridamole, disulfiram, doxazosin, elacridar, emetine, erythromycin, felodipine, fenofibrate, fentanyl, flavonoids, fluoxetine, fluphenazine, fluvoxamine, fucidin, gallopamil, glyburide, gramicidin D, grapefruit juice, garlic, green tea, haloperidol, hydrocortisone, hyroxisine, josamycin, ketoconazole, imipramine, itraconazole, ivermectin, ketoconazole, lanihidar, lansoprazole, levothyroxine, lidocaine, loperamide, lopinavir, loratadine, lovastatin, maprotiline, mefloquine, methadone, mibefradil, midazolam, mitomycin C, nefazodone, nelfinavir, nicardipine, nitrendipine, nobiletin, norverapamil, omeprazole, orange juice, ofloxacin, paroxetine, pantoprazole, phenothiazines, phenobarbital, piperine, pimozide, probenecid, progesterone, promethazine, propafenone, propranolol, hercetin, quinacrine, quinidine, quinine, reserpine, ritonavir, saquinavir, sertraline, simvastatin, spironolactone, sufentanil, tacrolimus, tamoxifen, tarichidar, telithromycin, terfenadine, testosterone, tetrabenazine, thioridazine, trifluoperazine, trifluopromazine, trimipramine, valinomycin, vanadate, venlafaxine, verapamil, vinblastine, FK506, RU486 (mifepristone), valspodar PSC 833, zosuhidar and 2npropylquinoline or their combinations; (b) reducing the dose or dose frequency of said P-gp inhibitor or avoiding the complete administration of said P-gp inhibitor before starting the administration of BIBW 2992 or its pharmaceutically acceptable salt, and (c) administering BIBW 2992, or a pharmaceutically acceptable salt thereof, to a subject having said cancer. 6. BIBW 2992 or a pharmaceutically acceptable salt thereof for use in the method according to claim 5, wherein the P-gp inhibitor is selected from cyclosporine, erythromycin, ketoconazole, itraconazole, quinidine, phenobarbital salt with quinidine, ritonavir, valspodar and verapamil. 7. BIBW 2992 or a pharmaceutically acceptable salt thereof for use in a method according to claim 5 or 6, wherein BIBW 2992 or a pharmaceutically acceptable salt thereof is administered without food which involves taking at least one hour before a meal until at least 3 hours after a meal.